1. Field of the Invention
The present invention relates generally to compositions and methods for lowering intraocular pressure and more particularly to the administration of inhibitors of ATP-sensitive K.sup.+ channel to the eye to lower intraocular pressure for the treatment of glaucoma.
Glaucoma is an ocular disorder that is often manifested as an elevated intraocular pressure. It is presently believed that such elevated pressure results from inadequate transport of the intraocular fluid from the anterior chamber, resulting in a detrimental pressure increase. If left untreated, glaucoma will eventually lead to loss of vision in the affected eye. Current treatment methods include forming small laser penetrations in the eye to release excess pressure, as well as the use of systemic and topical drugs for lowering intraocular pressure. Of particular interest to the present invention, topically applied drugs for the treatment of glaucoma include pilocarpine, a cholinergic; timolol maleate, a .beta.-adrenergic receptor blocking agent; epinephrine, an .alpha.- and .beta.-adrenergic receptor agonist; dipivefrin, a pro drug of epinephrine; and demecarium bromide, a cholinesterase inhibitor. While these drugs are generally effective, they can have significant adverse side effects, even when administered topically. Topical administration to the eye results in significant absorption leading to such undesirable systemic effects.
Elevated intraocular pressure can be caused by other conditions as well, such as impaired intraocular fluid transport caused by eye surgery, including surgery for glaucoma. No drugs are presently available for surgical implement of the intraocular fluid outflow.
Below normal intraocular pressure can also be a concern. Such reduced intraocular pressure can be caused by a variety of conditions, such as surgery for glaucoma, retinal detachment, uveitis, and the like. No drugs are presently available for the treatment of low intraocular pressure.
Therefore it would be desirable to provide additional drugs useful for the control of intraocular pressure, particularly for the treatment of glaucoma and other disorders related to elevated intraocular pressure, where such drugs have fewer or reduced side effects when compared to present drugs when topically applied. Drugs for the treatment of surgically induced elevated intraocular pressure as well as low (depressed) intraocular pressure would also be desirable. Such drugs should be safe, relatively non-toxic, and be amenable to incorporation in carriers and vehicles suitable for administration to the eye, either topically, by injection, or by ocular insert. These and other objectives will be met by the methods and compositions of the present invention, as described in more detail hereinafter.
2. Description of the Background Art
Compounds having various channel blocking activities, including inhibition of the ATP-sensitive K.sup.+ channel, have shown the ability to lower intraocular pressure, e.g. labetalol (an .alpha.- and .beta.-adrenergic blocker; Kogure et al. (1981) Arch. Int. Pharm. Ther. 250:109-122); phentolamine (an .alpha.-adrenergic blocker; Belmonte et al. (1987) Invest. Optal. Vis. Sci. 28:1649-1654); and antazoline (an H1-blocker; Krupin et al. (1980) Ophthal. 87:1167-1172). Quinine (a non-selective potassium channel blocker) has been suggested (without supporting data) as lowering intraocular pressure (U.S. Pat. No. 4,895,807 to Cherksey). U.S. Pat. No. 5,312,820, to Ashton suggests the use of certain carbonoy and oxycarbonyl derivatives of biphenylmethylamines for the treatment of hypertension and related disorders such as glaucoma. The Ashton compounds in some instances may contain an--(SO.sub.2 --NH--CO)--substituent group.
French patent application 2 585 574 describes the use of 4-phenyl-1,4-dihdro-pyridines for the treatment of glaucoma. The use of antihypertensive drugs for the treatment of glaucoma is suggested in U.S. Pat. No. 4,749,698 and published European applications 175 266; 180 994; and 235 544. The use of anti-inflammatory drugs for the treatment of glaucoma is suggested in U.S. Pat. No. 4,454,151. The use of potassium channel openers for the treatment of glaucoma is suggested in WO 89/10757. The use of dopamine-responsive agonists for the treatment of glaucoma is suggested in U.S. Pat. Nos. 4,722,933 and 4,657,925. The use of certain receptor agonists for the treatment of glaucoma is suggested in U.S. Pat. No. 5,011,846 and published European applications 329 903; 403 360; and 086 126. The use of tricyclic benzo fused compounds for the treatment of glaucoma is suggested in published European application 090 516. The use of angiotensin II receptor antagonists for the treatment of glaucoma is suggested in published European application 403 158. The use of inhibitors of angiotensin-converting enzyme (ACE) inhibitors for the treatment of glaucoma is suggested in U.S. Pat. No. 4,634,689 and WO 86/00896. The use of .alpha.2 antagonists for the treatment of glaucoma is suggested in U.S. Pat. No. 4,590,202 and published European application 080 779. The use of .beta.-blockers for the treatment of glaucoma is suggested in U.S. Pat. Nos. 5,003,115; 4,897,412; 4,935,422; 4,661,513; 4,647,590; 5,061,714; 4,990,668; 4,760,085; 4,766,151; 4,642,311; 4,582,855; 4,994,464; 4,897,417; 4,697,022; 4,526,893; published European applications 089 037; 437 030; 113 910; 087 378; and published PCT applications WO 87/03583; 87/03584; 83/00043. The use of carbonic anhydrase inhibitors for the treatment of glaucoma is suggested in U.S. Pat. Nos. 4,975,447; 4,914,111; 4,636,515; 4,975,448; 4,542,152; 5,039,802; 4,847,289; 4,894,390; and published European application 130 109. Other compositions and methods for treating glaucoma are described in U.S. Pat. Nos. 5,112,820; 4,871,742; 4,923,877; 4,346,106; 4,746,676; 5,134,146; 4,826,869; 5,075,323; 4,309,432; 4,906,467; 5,049,587; 5,013,837; 4,902,696; 4,559,361; 4,644,007; 5,034,406; 4,847,269; 4,001,132; 4,629,730; 459 568; Published PCT applications WO/06111; WO 90/02124; European patent publications 370 852; 132 190; 189 801; 338 507; Japanese patent publications 1-246220; 2-262518; French patent publication 2 593 395; Belgian patent publication 885.496.
EP 467 710 suggests that ATP-sensitive potassium channel blockers, such as sulfonyl urea and quinine, may be used to treat Parkinson's disease. EP 171 331 teaches quinine compositions. EP 467 709 (equivalent to U.S. Pat. No. 5,281,599) teaches the use of sulfonyl urea compounds for the treatment of Parkinson's disease. GB 2 177 913 teaches quinine compositions. WO 94/02142 teaches compositions including a sulfonyl urea moiety for treating hypertension.